Phylogenetic relationships among organisms have been demonstrated many times, and studies from a diversity of prokaryotic and eukaryotic organisms suggest a more or less gradual evolution of biochemical and physiological mechanisms and metabolic pathways. Despite different evolutionary pressures, proteins that regulate the cell cycle in yeast, nematode, fly, rat, and man have common chemical or structural features and modulate the same general cellular activity. Comparisons of human gene sequences with those from other organisms where the structure and/or function may be known allow researchers to draw analogies and to develop model systems for testing hypotheses. These model systems are of great importance in developing and testing diagnostic and therapeutic agents for human conditions, diseases and disorders.
Fatty acids are required for phospholipid, glycolipid, hormone, and intracellular messenger formation; to anchor proteins to membranes; and as fuel molecules. Most cells can synthesize fatty acids from acetate substrates, though many mammalian cells also obtain fatty acids by hydrolysis of triglycerides. Synthesis of phospholipids primarily occurs on the surface of the smooth endoplasmic reticulum. Although most cells constitutively form fatty acids, the level of synthesis varies with the needs of the cell. During phases of rapid cell division, membrane formation requires enhanced production of phospholipids. Animals that have fasted and are then fed high-carbohydrate, low-fat diets show marked increases in the amount and activity of enzymes responsible for fatty acid synthesis. Increased synthesis of long chain fatty acids also occurs in multiple common neoplasms, including those arising in the breast, prostate, ovary, colon, and endometrium. Overexpression of fatty acid synthase (FAS), a major enzyme of fatty acid biosynthesis, is a marker for poor prognosis in breast tumors and has been shown to be important for tumor growth (Moncur et al. (1997) Proc. Natl. Acad. Sci. USA 95:6989-6994).
The transcriptional regulation of enzymes involved in fatty acid synthesis is associated with Spot 14 (S14) protein. S14 is a small, acidic nuclear protein with a carboxy-terminal "zipper" domain involved in homodimer formation. It is expressed in tissues that produce lipids for use as metabolic fuels, such as lactating mammary tissue, white and brown adipose tissue, and liver. The expression of S14 is increased in response to insulin, dietary carbohydrates, glucose, and thyroid hormone and reduced in response to glucagon, fasting, and in diabetes mellitus. Expression of antisense oligonucleotides has shown S14 induces tissue-specific expression of several lipogenic enzymes including FAS and ATP citrate-lyase. The S14 gene is located on chromosome 11 at position q13.5, a chromosoinal region amplified in approximately 20% of breast cancers, and is expressed in several breast cancer-derived cell lines and in a majority of primary breast tumors (Cunningham et al. (1998) Thyroid 8:815-825; Liaw and Towle (1984) J. Biol. Chem. 259:7253-7260; Brown et al. (1997) J. Biol. Chem. 272:2163-2166; and Moncur, supra).
A zebrafish gastrulation protein, G12, shares features with S14 including acidic pI (.about.4.9) and nearly identical size (.about.17 kDa). The sequence similarity between the two proteins is strongest at the carboxy terminus, including the zipper domain. G12 is expressed in an outer, enveloping layer of cells (EVL), analogous to the mammalian trophectoderm, during a period in gastrulation in which the EVL layer expands to cover the developing, embryonic deep cell layer. During this stage, apical membrane turnover in the EVL increases and raises the requirement for phospholipids used in plasma membranes (Conway (1995) Mech. Dev. 52:383-391; Fink and Cooper (1996) Dev. Biol. 174:180-189).
The discovery of a polynucleotide encoding a new mammalian protein satisfies a need in the art by providing new compositions which are useful in the characterization, diagnosis, prevention, and treatment of cell proliferative and lipid disorders.